KR20130080813A - Process for the preparation of the l-arginine salt of perindopril - Google Patents

Abstract

.The present invention relates to a process for the preparation of compounds of formula (I):

.

Description

The manufacturing method of L-arginine salt of perindopril {PROCESS FOR THE PREPARATION OF THE L-ARGININE SALT OF PERINDOPRIL}

The present invention relates to a process for the preparation of the perindopril L-arginine salt of formula (I):

Perindopril and its pharmaceutically acceptable salts, and more particularly their L-arginine salts, have valuable pharmacological properties. Its main property is the inhibition of angiotensin I converting enzyme (or kininase II), on the one hand the conversion of decapeptide angiotensin I to octapeptide angiotensin II (vascular contractor) and on the other hand inactive peptide of bradykinin (vascular dilator) This property makes it possible to prevent decomposition of the furnace. Both actions contribute to the beneficial effect of perindopril in cardiovascular disease, more particularly arterial hypertension, heart failure and stable coronary artery disease.

Perindopril, its preparation and its use in therapeutic agents are described in European patent specification EP 0 049 658.

The L-arginine salt of perindopril was first described in European Patent Specification EP # 1 # 354 # 873. The alpha and beta crystal forms of the L-arginine salts of perindopril are described in European patent specifications EP 1 989 182 and EP 2 016 051. Gamma crystal forms of the L-arginine salt of perindopril are described in patent application WO 2009/157018.

In view of the pharmaceutical value of perindopril L-arginine, it was very important to obtain it in good yield and good purity.

More particularly, the problem is to find conditions under which the conversion of perindopril to a salt with L-arginine occurs exactly and to easily separate the L-arginine salt of perindopril from the reaction mixture.

In addition, most of the tests performed by the inventors to obtain L-arginine salts of perindopril starting with perindopril and L-arginine resulted in products of gelatinous appearance that are very difficult to process later.

Patent specification EP 1 279 665 describes a process for obtaining perindopril salts, more particularly tert-butylamine salts. The described method avoids the cyclization impurities typically generated from peptide coupling, while N- [1- (S) -ethoxycarbonyl-butyl to (2S, 3aS, 7aS) -2-carboxyperhydroindole moiety ]-(S) -alanine moiety enables coupling. Thus, the tert-butylamine salt of perindopril is obtained in Example 3 of EP # 1 279 665 with good yield (80%) and good purity (99%).

The inventors applied the method described in Example 3 of EP 1 279 665 to the preparation of the L-arginine salt of perindopril. However, replacing tert-butylamine with (L) -arginine and otherwise following the procedure of EP 1 279 665 did not make it possible to obtain the L-arginine salt of perindopril in good yield (Comparative Example A Reference).

Surprisingly, when the conversion to salt is performed in a solvent system selected from acetonitrile / dimethyl sulfoxide, ethyl acetate / dimethyl sulfoxide and acetonitrile / dimethyl sulfoxide / toluene instead, the L-arginine salt of perindopril is in good yield. And good purity, and separation is greatly promoted.

More particularly, the present invention provides a two-component mixture of acetonitrile and dimethyl sulfoxide, a two-component mixture of ethyl acetate and dimethyl sulfoxide, acetonitrile, dimethyl sulfoxide and at a temperature of 10 to 100 ° C., preferably 40 to 80 ° C. After reaction between perindopril and L-arginine in a solvent system selected from a three-component mixture of toluene, the L-arginine salt thus obtained is isolated by filtration to prepare the L-arginine salt of perindopril It is about how to.

According to an embodiment of the present invention, the perindopril (free acid) used in the reaction is an organic solvent or a system of organic solvents, preferably at a temperature of -20 ° C to 80 ° C, preferably -10 to 40 ° C. N- [1- (S) -ethoxycarbonyl-butyl]-(S) -alanine of formula (II) in an acetonitrile, ethyl acetate or dichloromethane is the activator, preferably N, N'-car After reaction with carbonyldiimidazole, phosgene, triphosgene, (1,1'-carbonyldi (1,2,4-triazole) or di (N-succinimidyl) carbonate, Obtained by reacting an intermediate compound of formula (III) with (2S, 3aS, 7aS) -2-carboxyperhydroindole at a temperature of 0 ° C to 80 ° C, preferably 5 to 40 ° C:

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"Activator" is a formula X ₂ C wherein X is a leaving group, for example a halogen atom or tosylate, mesylate, imidazolyl, 1,2,4-triazolyl, succinimidyl or a substituted or unsubstituted alkoxy group It is understood to mean a compound of = 0.

When the activator is N, N'-carbonyldiimidazole, the amount of N, N'-carbonyldiimidazole is preferably N- [1- (S) -ethoxycarbonyl-butyl]-(S) 0.8 to 1.2 moles per mole of alanine.

The amount of (2S, 3aS, 7aS) -2-carboxyperhydroindole is preferably 0.8 to 1.2 moles per mole of N- [1- (S) -ethoxycarbonyl-butyl]-(S) -alanine.

According to another embodiment of the present invention, perindopril (free acid) used in the reaction is obtained by desaltification of perindopril tert-butylamine by the action of an acid.

"Dissolation of perindopril tert-butylamine" is understood to mean returning the perindopril tert-butylamine to perindopril in the free acid form.

The following examples illustrate the invention.

This example does not result in all pure delta crystal forms.

Abbreviation :

CDT (1,1'-carbonyldi (1,2,4-triazole))

DMSO dimethyl sulfoxide

DSC (di (N-succinimidyl) carbonate)

HPLC high performance liquid chromatography

Filtration is expressed in a standard way: time and filtration area m ² kg of liquid per filter.

Example 1 : L-arginine salt of perindopril-starting with perindopril (free acid) in a bicomponent mixture of acetonitrile / DMSO 25/75 without seeding

Perindopril (12.5 g, 1 eq.) And L-arginine (5.32 g-0.9 eq) were suspended in a mixture of acetonitrile (20 g, d = 0.787) and DMSO (61 g, d = 1.100). The reaction mixture was heated at 50 ° C. overnight. The product was then separated by filtration on frits. The filter cake was washed and dried.

Perindopril arginine (14.5 g) was obtained in 79% yield compared to perindopril. The separated crystalline phase is a delta phase. The HPLC properties of the isolated product exceed 99.0%.

The filtration rate of the mother liquor is about 6000 kg / h / m ² .

The L-arginine salt of perindopril thus obtained is delta crystalline. This form is measured using a diffractometer with a copper cathode, expressed in terms of the interplanar distance d, the Bragg's angle 2 theta, and the relative intensity expressed as a percentage relative to the strongest line. The line powder diffraction diagram has:

Each line is considered to have an accuracy of ± 0.2 ° at 2-theta.

1: Diffractogram of the delta form of perindopril L-arginine.

Example 2 : L-arginine salt of perindopril-starting with perindopril (free acid) in a bicomponent mixture of acetonitrile / DMSO 25/75 using seeding

Perindopril (100 g, 1 eq.) And L-arginine (42.6 g, 0.9 eq.) Are suspended in a mixture of acetonitrile (220 g, d = 0.787) and dimethyl sulfoxide (630 g, d = 1.100). I was. The reaction mixture was heated at 70 ° C. for 3 hours, seeded with 2% on delta and then cooled to 40 ° C. over 1 hour. The mixture was kept at 40 ° C. for 18 hours with stirring and then cooled to 20 ° C. over 1 hour. The product was then separated by filtration. The filter cake was washed and dried.

Perindopril (L) -arginine (119 g) was obtained in 79% yield over perindopril. The HPLC properties of the isolated product exceed 99.0%.

The filtration rate of the mother liquor is about 6000 kg / h / m ² .

Example 3 : (2S, 3aS, 7aS) -2-carboxy-perhydroindole and N- [1- (S) -ethoxycarbonyl-butyl]-(by activation with N, N'-carbonyldiimidazole S) -General procedure for the production of perindopril (free acid) starting from alanine.

N- [1- (S) -ethoxycarbonyl-butyl]-(S) -alanine (65 g, 1 eq.) And N, N'-carbonyldiimidazole (48 g, 1 eq.) After introduction, acetonitrile (500 g) was added. Thereafter, the reaction mixture was stirred for 3 hours at a temperature of less than +10 ° C.

The reaction mixture was poured into (2S, 3aS, 7aS) -2-carboxyperhydroindole (50 g, 1 eq.) And the amount of fresh acetonitrile (80 g) was used to rinse the device.

The reaction mixture was then stirred at a temperature below + 10 ° C. for 5 hours and then clarified on a filter to yield a clear solution.

Example 4 : L-arginine salt of perindopril-starting with (2S, 3aS, 7aS) -2-carboxyperhydroindole in a two-component mixture of acetonitrile / DMSO 50/50 using seeding

A solution in acetonitrile of perindopril (100 g of product) synthesized according to the general procedure of Example 3 at 50 ° C. was dissolved in L-arginine (44.3 g, 0.85 eq.) In DMSO (540 g, d = 1.100). Pour into suspension to give perindopril L-arginine (110 g) and seed the reaction mixture with 2% of the delta crystalline form (compound of Example 1). The mixture was kept at 50 ° C. for 15 hours with stirring and then cooled to 20 ° C. at a rate of 0.5 ° C./min. The suspension was filtered using a filtration cell. The yield was 75% compared to the perindopril used. The properties of the isolated product exceed 99.0% according to HPLC.

The filtration rate of the mother liquor is about 5000 kg / h / m ² .

Example 5 : L-arginine salt of perindopril-starting from (2S, 3aS, 7aS) -2-carboxyperhydroindole in a two-component mixture of acetonitrile / DMSO 75/25 using seeding

Aceto of perindopril (38 g of product) synthesized according to the general procedure of Example 3 by addition of L-arginine (17 g, 0.85 eq.) Suspended in dimethyl sulfoxide (78 g) at a temperature of 40 ° C. Perindopril L-arginine (42 g) was obtained by pouring the solution in nitrile and then seeding 4% by weight of the delta-type perindopril L-arginine (compound of Example 1). Filtration was carried out at 40 ° C. using a filtration cell.

The yield is 73% compared to the perindopril used. The properties of the isolated product exceed 99.0% according to HPLC.

The filtration rate of the mother liquor is about 5700 kg / h / m ² .

Example 6 : L-arginine salt of perindopril-starting with (2S, 3aS, 7aS) -2-carboxyperhydroindole and triphosgene

N- [1- (S) -ethoxycarbonyl-butyl]-(S) -alanine (20 g, 1 eq.) And Na ₂ HPO ₄ .12H ₂ O (43 g, 1.3 eq.) Suspended in (212 g). After the reaction mixture was heated to reflux, a solution of triphosgene (9.55 g, 0.35 eq.) In dichloromethane (64 g) was poured into it. After liquid / liquid washing of the organic phase with water, dichloromethane is evaporated to give activated N- [1- (S) -ethoxycarbonyl-butyl]-(S) -alanine (22 g) of formula (III). Generated. Thereafter it was dissolved in acetonitrile (180 g). The solution is poured into (2S, 3aS, 7aS) -2-carboxyperhydroindole (15 g, 1 eq.) And then the reaction mixture is present in the presence of triethylamine (9.15 g, 1 eq.) At a temperature below 10 ° C. After stirring for about 5 hours under, it was clarified through a filter to give a clear solution. L-arginine (14.5 g, 0.90 eq.) Suspended in DMSO (180 g) at a temperature of 50 ° C. was added to give the L-arginine salt of perindopril. After about 5 hours of contact time, the mixture was seeded with 2% of the delta type, then stirred at 50 ° C. overnight and filtered using a filtration cell.

Perindopril L-arginine (43 g) was obtained in 89% yield as compared to (2S, 3aS, 7aS) -2-carboxyperhydroindole (seed deduction). The HPLC properties of the isolated product exceed 99%.

The filtration rate of the mother liquor is about 2000 kg / h / m ² .

Example 7 : L-arginine salt of perindopril-acetonitrile / dimethyl using seeding Sulfoxide / Toluene 30/40/30 3-component  In mixture Perindopril  3rd From butylamine  start

Perindopril tert-butylamine (103 g, 1.00 eq.) And sodium chloride (5.84 g) were suspended in toluene (268 g, d = 0.867). Stir at ambient temperature.

A solution of hydrochloric acid (57.8 mL, # 4 N, 1 eq.) Was added. Stir at ambient temperature for 40 minutes. The toluene phase was separated from the aqueous phase.

The aqueous phase was washed with toluene (2 x 90 g, d = 0.867).

In this step, perindopril is present in solution in toluene at a concentration of 16% w / w.

L-Arginine (36.6 g, 0.90 eq.) And dimethyl sulfoxide (566 g, d = 1.100) were added and the reaction mixture was heated at 50 ° C for 5 hours. Acetonitrile (405 g, d = 0.787) was added and 2% by weight of delta-type perindopril L-arginine (compound of Example 1) was seeded.

After the suspension was stirred for 17 hours, the temperature was brought to 30 ° C. over 30 minutes. After stirring for 2 hours, the product was separated by filtration. The filter cake was washed and dried.

Perindopril L-arginine (95 g) was obtained in 75% yield compared to perindopril tert-butylamine. The HPLC properties of the isolated product exceed 99.8%.

The filtration rate of the mother liquor is about 4000 kg / h / m ² .

Example 8 : L-arginine salt of perindopril starting with perindopril (free acid) in a three-component mixture of acetonitrile / DMSO / toluene 30/40/30 using seeding

Lyophilized perindopril (8.3 g, 1 eq.) Was dissolved in a mixture of toluene (43 g) and DMSO (55 ng). L-arginine (3.9 g, 1 eq.) Was introduced in the form of a suspension in acetonitrile (40 g) and the entire batch was heated at 50 ° C.

3% of the delta-type perindopril arginine was seeded in the reaction mixture, and the suspension was stirred at 50 ° C. for 22 hours.

The product was separated by filtration.

Perindopril L-arginine (9 g) was obtained in 73% yield compared to perindopril. The HPLC properties of the isolated product exceed 99%.

Example 9 : L-arginine salt of perindopril-of ethyl acetate / DMSO 55/45 using seeding 2-component  In mixture Perindopril  3rd From butylamine  start

Perindopril erbumin (200 g, 1 eq.), Methyltetrahydrofuran (700 g) and methanesulfonic acid (43.5 g, 1 eq.) Were loaded into the reactor.

Insoluble material was filtered off and L-arginine (78.8 g, 1 eq.) And DMSO (500 g) were added to the solution.

Methyltetrahydrofuran was distilled off and heated at 70 ° C. for 1 hour.

Ethyl acetate (600 g) was added and seeded with 2% of delta crystalline perindopril arginine.

Cooled to 25 ° C. over 4 hours, filtered, and washed the product with a mixture of ethyl acetate / DMSO. Perindopril L-arginine (217 g, seed deduction) was obtained in 88% yield compared to perindopril. The HPLC properties of the isolated product exceed 99%.

The filtration rate of the mother liquor is at least 1500 kg / h / m ² .

Example 10 : L-arginine salt of perindopril starting with perindopril (free acid) in a three-component mixture of acetonitrile / DMSO / toluene 45/50/5 using seeding

Lyophilized perindopril (30 g, 1 eq.), DMSO (100 g) and L-arginine (13.8 g, 1 eq.) Were loaded into the reactor. The mixture was heated at 70 ° C. for 2 hours.

A mixture of acetonitrile (90 g) and toluene (10 g) was added and seeded 2% of the delta crystalline perindopril arginine. The suspension was stirred at 70 ° C. for 2 hours.

Cooled to 25 ° C. over 4 hours, filtered, and washed the product with acetonitrile and DMSO.

Perindopril L-arginine (41 g, seed deduction) was obtained in 92% yield over perindopril. The HPLC properties of the isolated product exceed 99%.

The filtration rate of the mother liquor is at least 1500 kg / h / m ² .

Comparative Example A Adaptation of the procedure of Example 3 of EP 1 279 665 to obtain the L-arginine salt of perindopril

The reactor was previously cooled to 0 ° C. N- [1- (S) -ethoxycarbonyl-butyl]-(S) -alanine (80 g-1 eq.) And dichloromethane (1325 g, d = 1.325) were introduced. N, N'-carbonyldiimidazole (71.5 g - 1.2 eq.) And 0.336 L of dichloromethane were added to the mixture. The temperature of the mixture was brought to -5 ° C before addition of (2S, 3aS, 7aS) -2-carboxyperhydroindole (81 g-1.3 eq.). After a contact time of 2 hours 30 minutes, the mixture was dried and then dissolved in water (1200 g, d = 1.00). After acidification of the aqueous phase (using 185 ml of 4N HCl solution), the solution was extracted with dichloromethane (2517.5 g, d = 1.325) and the aqueous phase was saturated with NaCl. The organic phase was dried and the residue from drying was dissolved in ethyl acetate (1176.6 g, d = 0.902). Then L-arginine (68 g-1.06 eq.) Was added and the mixture was kept at 50 ° C overnight with stirring.

Filtration of the mixture has been found to be impossible, since the solid has a sticky density. Solids were separated from the reactor by decomposition of the tank.

Yield (determined by titration): 1.6%.

Comparative Example B : According to Example 6 of Patent Application WO # 2009/157018

Perindopril (30 g) and L-arginine (13.8 g) were suspended in toluene (130 g, d = 0.867) at ambient temperature. The mixture was refluxed for 1 hour. Thereafter, acetonitrile (1180.5 g, d = 0.787) was added at 80 ° C. After maintaining stirring for 1 hour at this temperature, the suspension was filtered using a cell under 0.3 bar of nitrogen.

The average filtration rate of the mother liquor was measured at 100 kg / h / m ² . The isolated product had a sticky density and the color was pale pink. The yield based on weight was 46.5%. The HPLC properties of the isolated product were about 83%.

1: Diffractogram of the delta form of perindopril L-arginine.

Claims (6)

Perindo in a solvent system selected from a two-component mixture of acetonitrile and dimethyl sulfoxide, a two-component mixture of ethyl acetate and dimethyl sulfoxide, a three-component mixture of acetonitrile, dimethyl sulfoxide and toluene at a temperature of 10 to 100 ° C. Process for the preparation of the perindopril L-arginine salt of formula (I) after the reaction between prill and L-arginine, by which the L-arginine salt thus obtained is separated by filtration:

. A compound according to claim 1, wherein N- [1- (S) -ethoxycarbonyl-butyl]-(S)-of formula (II) After reacting alanine with an activator of formula X ₂ C═O wherein X is a leaving group, the intermediate compound of formula (III) obtained thereby is reacted with (2S, 3aS, 7aS) -2-carboxyperhydroindole with 0 to 80 A process for preparing the perindopril L-arginine salt, wherein the reaction is carried out at a temperature of < RTI ID = 0.0 >

. 3. The active agent of claim 2, wherein the active agent is N, N'-carbonyldiimidazole, phosgene, triphosgen, (1,1'-carbonyldi (1,2,4-triazole) or di (N). A process for preparing the perindopril L-arginine salt, which is -succinimidyl) carbonate. 4. The active agent according to claim 3, wherein the active agent is N, N'-carbonyldiimidazole and the amount of N, N'-carbonyldiimidazole is N- [1- (S) -ethoxycarbonyl-butyl]-. A process for preparing the perindopril L-arginine salt, which is 0.8 to 1.2 moles per mole of (S) -alanine. The amount of (2S, 3aS, 7aS) -2-carboxyperhydroindole is N- [1- (S) -ethoxycarbonyl-butyl]-(S) according to any one of claims 2 to 4. A process for preparing the perindopril L-arginine salt, which is from 0.8 to 1.2 moles per mole of alanine. 2. The method according to claim 1, wherein perindopril is obtained by disaltification of perindopril tert-butylamine by the action of an acid, and then the perindopril obtained thereby is subjected to the method of claim 1. Accordingly reacting with L-arginine to prepare a perindopril L-arginine salt.

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